Supply Chains Without Borders

Pharmaceutical manufacturing has become a global business, transforming the way drugs are produced, regulated, and marketed. Along with many benefits, this development carries added risks, as illustrated by the Baxter heparin case. It may make economic sense to shift heparin production to a land with millions of pigs and cheap labor. But that can open the door to product contamination or fraud.

When Baxter International was hit by hundreds of serious adverse event reports earlier this year, including up to 20 deaths, it took the manufacturer, its supplier, and the Food and Drug Administration months to uncover the "root cause" of the problem. Baxter had to recall thousands of vials and shut down production of heparin, a blood thinner used by thousands of patients undergoing surgery and kidney dialysis. Soon after, similar adverse events prompted recall of heparin made in Germany, but with ingredients from a different supplier.

Although the cause of contamination was initially a mystery, the fact that Baxter's API (active pharmaceutical ingredient) came from China quickly captured national attention. With unsafe Chinese food, toothpaste, and drugs making headlines, the media had a field day running stories on how small Chinese operators process an extract from pigs' intestines into crude heparin.

The Heparin Contamination Hunt

Compounding the problem was the unexpected discovery that FDA never inspected API manufacturer Changzhou SPL, nor did Chinese regulators (see sidebar). At a contentious hearing in February before the House Appropriations subcommittee that approves FDA funding, chair Rosa DeLauro (D-CT) termed the heparin-inspection error one more example of "FDA's myriad failures" in dealing with drug safety issues. Rep. Frank Pallone (D-NJ), chairman of the House Energy and Commerce Health subcommittee, said the inspection error reflects "sloppy work" and "carelessness that seriously jeopardized the health of American patients."

Obsolete Oversight

Certainly the heparin debacle highlights FDA's difficulties in overseeing a fast-expanding volume of imported drugs and medical products. FDA officials admit that their tracking system is so obsolete that they have only a vague idea of what drugs are manufactured where and which overseas facilities have been inspected. The House Energy and Commerce Committee held a hearing last November on FDA's inability to monitor imported drugs and active ingredients, and the heparin debacle has fueled that ongoing investigation.

The case also focused attention on FDA's preapproval inspection (PAI) program, which has narrowed in recent years as part of agency efforts to reduce redundant site visits and to target inspections to higher-risk products. E&C subcommittee chair Bart Stupak (D-MI) said that if FDA fails to adequately assess new drug production, Congress might consider legislative changes that would "prohibit the marketing of any drug from a plant that has not been properly inspected."

Such a statutory PAI requirement would further stress FDA's depleted field inspection operations. About 80 percent of drug APIs come from foreign manufacturers, reported Janet Woodcock, FDA deputy commissioner and acting director of the Center for Drug Evaluation and Research (CDER), at the Appropriations hearing. However, the agency now inspects only about 10 percent of foreign drug producers due to inadequate field force funding.

"We have raised red flags for years" about the overseas shift in drug manufacturing and clinical trials," Woodcock commented. Although imports of finished drugs now are much lower than for APIs, she predicted that this "is going to change" as operators in "many regions of the world have indicated that they want to take over drug manufacturing." FDA says it conducted a record 1,000 inspections of overseas facilities last year. But it cannot sustain that volume without hundreds of additional inspectors and an updated data system to better control drug imports into the United States and to ensure product quality.

A coalition of agency advocates is campaigning to boost FDA's budget significantly, but Congressional support is mixed. While DeLauro backed added funding to support FDA's mission, she also insisted that FDA first improve its management and operations. "All this agency ever does is cry about resources," she complained, noting "serious negligence" in using what it does have to enforce regulations.